SOFA Score in relation to Sepsis: Clinical Implications in Diagnosis, Treatment, and Prognostic Assessment.
To analyze the clinical significance of the sequential organ failure assessment (SOFA) score in the diagnosis, treatment, and prognostic assessment of sepsis. 140 patients with sepsis from January 2020 to January 2021 were selected as the observation group, and 40 healthy people were selected as the control group. The observation group was divided into mild group, severe group, and septic shock group by single blind grouping according to the condition of the disease, and they were also divided into survival group and death group according to the prognosis. Collect the fasting venous blood of the subjects in each group in the morning, compare the levels of total bilirubin (TBIL), blood creatinine (CR), and platelet count (PLT) in each group, and record and compare the patients' respiratory system oxygen partial pressure/inhaled oxygen concentration (po2/fio2), acute physiology and chronic health scoring system II (APACHE II), sequential organ failure assessment (sofa) score, q-SOFA score, and △SOFA score; Pearson analysis was used to analyze the correlation between SOFA score and other indicators; multivariate logistic regression was used to analyze the prognostic risk factors of patients with sepsis; receiver-operating characteristic curve (ROC) was used to analyze the value of SOFA score alone and in combination in the diagnosis, condition, and prognosis of sepsis. There were significant differences in Apache II score, SOFA score, q-SOFA score map, po2/fio2, PLT, GCS, TBIL, and serum creatinine (SCR) between the control group and the observation group (P < 0.05). There were significant differences in Apache II score, SOFA score, q-SOFA score, mean arterial pressure (map) po2/fio2, PLT, Glasgow Coma Score (GCS), TBIL, SCR, and △SOFA score among patients in mild, severe, and septic shock groups (P < 0.05). There were significant differences in age, Apache II score, SOFA score, q-SOFA score, map, po2/fio2, PLT, GCS, TBIL, SCR, and △SOFA score between survival group and death group (P < 0.05). SOFA score and q-SOFA score were significantly positively correlated with TBIL and SCR and significantly negatively correlated with po2/fio2 and PLT; △SOFA score was significantly negatively correlated with TBIL and SCR and significantly positively correlated with map, po2/fio2, PLT, and GCS. Apache II score, SOFA score, and q-SOFA score were independent risk factors for sepsis patients, and △SOFA score, po2/fio2, and GCS score were protective factors (P < 0.05). ROC curve analysis showed that the AUC of sepsis combined with SOFA score and q-SOFA score was 0.880; the AUC of sepsis assessed by SOFA score, q-SOFA score, and △SOFA score was 0.929; the AUC of sepsis prognosis assessed by SOFA score, q-SOFA score, and △SOFA score was 0.900. SOFA score, q-SOFA score, and △SOFA score were abnormally expressed in patients with sepsis and were risk factors for the severity of the patient's condition and prognosis. The SOFA score, q-SOFA score, and △SOFA score were risk factors for the severity and prognosis of patients with sepsis and had some value in diagnosing sepsis and assessing the condition and prognosis, of which the combined value of the three was higher.


Quantitative and qualitative changes in serum oligopeptide components of patients with end stage malignant tumour disease.
A number of changes in peptide components could be demonstrated in sera of patients with end stage malignant diseases. Total and free alfa amino-N content of such sera was shown to be significantly higher than those in sera of patients with no sign of malignancy. In addition, a significant increase was found in one of the serum fraction obtained by Sephadex G-25 chromatography. This increase was shown to be due to an increase in the amount of one of the isotachophoretically separated serum components of anionic character as well as to the appearance in sera of tumour bearing patients of two additional isotachophoretic components never detected in non tumour bearing patients. Based on their chromatographic behavior as well as on observations made in earlier experiments, the peptide nature of the two isotachophoretic serum components seemingly characteristic of sera of tumour bearing patients is highly probable.


Interventional planning of liver resections: an overview.
Liver cancer is the third most common type of cancer. Among available treatment options, a surgical resection offers the best prognosis for long-term survival. It is important that such a surgical procedure is carefully prepared. Modern computer technology offers convenient ways to simulate different resection scenarios and help to determine the best treatment for a given case. This paper provides a non-exhaustive overview of existing computer-based systems for interventional planning of liver resections. They are reviewed according to their medical use case, e.g. if they support typical or atypical resections.


Circulating IGF-I levels in monitoring and predicting efficacy during long-term GH treatment of GH-deficient adults.
To investigate the effects of long-term GH in GH-deficient adults, as predicted by IGF-I levels. Patients received GH, 5 microg/kg per day for 1 Month and 10 microg/kg per day for another 12-30 Months. Changes in body composition, cardiac structure/function, serum lipids and quality of life were measured. There was a significant increase in lean body mass (LBM) (2.21 kg; P<0.0001) after 6 Months, which was sustained throughout treatment. A larger increase occurred in males than females (2.97 vs 1.19 kg; P<0.0001). Total fat mass was reduced (2.56 kg; P<0.0001 (3.26 kg males, 1.63 kg females)). Responsiveness to GH varied greatly, but LBM changes correlated with IGF-I changes (P<0.004). Furthermore, thinner patients experienced greater and progressive LBM increases. There was an increase in ejection fraction (3.85+/-9.95%; P=0.0002) after 6 Months, sustained to 18 Months. These cardiac effects were equal for males and females, and did not correlate with IGF-I levels. Serum low-density lipoprotein/high-density lipoprotein ratios decreased within 6 Months, and were sustained thereafter. Quality of life improved significantly after 6 Months, an effect that was sustained/enhanced as treatment continued. No major adverse events were identified. Improved body composition is both reflected by IGF-I changes and predicted inversely by baseline adiposity. Other effects of GH replacement on cardiac function, dyslipidaemia and quality of life, however, do not correlate with circulating IGF-I concentrations. Our findings validate the importance of sustained GH therapy, but caution on the interpretation of IGF-I levels in monitoring the long-term effects of GH treatment.


PID and PLC units for the real-time control of sewer systems.
Moveable gates for the real-time control (RTC) of sewer systems storage capacities are usually operated by controllers which, on the basis of local water level or flow velocity measurements, calculate the regulation errors of the monitored variables, determining the necessary regulator movements to lead the flow conditions to the desired set point. In this paper the results of an investigation on the influence of proportional-integral-derivative (PID) controllers and programmable logic controllers (PLC) for the RTC of moveable sluice gates positioned into sewer systems are presented. The analysis of response time, damping and regulation errors provided information on the PID parameter calibration values and on the PLC control function performances. A comparison between the two kind of controllers has also been carried out.


Pseudomonas fluorescens JH 70-4 promotes pb stabilization and early seedling growth of sudan grass in contaminated mining site soil.
A bacterial strain (JH 70-4) exhibiting plant growth promoting characteristics (indoleacetic acid production and 1-aminocyclopropane-1-carboxylate deaminase activity), as well as heavy metal(loid) (HM) tolerance and Pb precipitation, was isolated from HM-contaminated soil at an abandoned mine site. The bacterium was identified as Pseudomonas fluorescens based on 16S rDNA sequencing. The JH 70-4 strain induced precipitation of Pb as PbS nanoparticles, confirmed by X-ray diffraction. Solution pH, incubation time, and Pb concentration influenced removal and PbS formation. Inoculating contaminated soil with JH 70-4 decreased Pb availability; exchangeable Pb decreased while organic- and sulphide-bound Pb increased. The toxicity characteristic leaching procedure showed a 65% decrease in Pb in leachate 60 d after inoculating soil with JH 70-4. Shoot and root lengths of Sudan grass grown in the inoculated soil were greater than in the uninoculated soil. Findings suggest that microbial Pb fixation is a viable strategy for remediating soil and promoting plant growth for phytostabilization of contaminated sites.


The Postconcussion Symptom Scale: utility of a three-factor structure.
This study aimed to determine the factor structure of a 19-item Postconcussion Symptom Scale and to examine associations between factor scores and sex, previous history of concussion, and length of time since injury. This is a retrospective medical record review of pediatric patients with concussion seen in a sports medicine clinic from April 2008 to September 2012. We performed an exploratory factor analysis (EFA) followed by a confirmatory factor analysis (CFA). ANOVA and regression analysis were used to examine associations between factor scores and sex, previous history of concussion, mood disorder, anxiety disorder or attention-deficit disorder, and length of time since injury. EFA supported a three-factor solution for postconcussive symptoms employing 18 of the original 19 scale items. Factor 1 consisted of eight cognition-related items, factor 2 consisted of six somatic-related items, and factor 3 consisted of four emotional-related items. CFA results confirmed the unidimensionality of factors 1 (neurocognitive), 2 (somatic) and 3 (emotional), with factor 3 being considered borderline. Females and patients with anxiety disorders had significantly worse (higher) scores on all three factors. Patients seen >14 d after the concussive injury had worse (higher) factor 3 (emotional) scores than those seen <14 d after the injury. There was no significant difference in postconcussive symptom factor structures between those with and without a previous history of concussion. Our investigation demonstrates a consistent symptom 3-factor structure of the Postconcussion Symptom Scale in pediatric patients with concussions. Females and patients with anxiety disorders had higher scores than males for all three factors. Patients seen >14 d after concussive injury had higher scores for emotional symptoms, suggesting that prolonged concussion symptoms may affect emotional health.


Cerebellar and basal ganglia motor network predicts trait depression and hyperactivity.
In the human brain, the cerebellum (CB) and basal ganglia (BG) are implicated in cognition-, emotion-, and motor-related cortical processes and are highly interconnected, both to cortical regions via separate, trans-thalamic pathways and to each other via subcortical disynaptic pathways. We previously demonstrated a distinction between cognitive and motor CB-BG networks (CCBN, MCBN, respectively) as it relates to cortical network integration in healthy young adults, suggesting the subcortical networks separately support cortical networks. The CB and BG are also implicated in the pathophysiology of schizophrenia, Parkinson's, and compulsive behavior; thus, integration within subcortical CB-BG networks may be related to transdiagnostic symptomology. Here, we asked whether CCBN or MCBN integration predicted Achenbach Self-Report scores for anxiety, depression, intrusive thoughts, hyperactivity and inactivity, and cognitive performance in a community sample of young adults. We computed global efficiency for each CB-BG network and 7 canonical resting-state networks for all right-handed participants in the Human Connectome Project 1200 release with a complete set of preprocessed resting-state functional MRI data (N = 783). We used multivariate regression to control for substance abuse and age, and permutation testing with exchangeability blocks to control for family relationships. MCBN integration negatively predicted depression and hyperactivity, and positively predicted cortical network integration. CCBN integration predicted cortical network integration (except for the emotional network) and marginally predicted a positive relationship with hyperactivity, indicating a potential dichotomy between cognitive and motor CB-BG networks and hyperactivity. These results highlight the importance of CB-BG interactions as they relate to motivation and symptoms of depression.


UCP2 inhibition induces ROS/Akt/mTOR axis: Role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism.
Several studies indicate that mitochondrial uncoupling protein 2 (UCP2) plays a pivotal role in cancer development by decreasing reactive oxygen species (ROS) produced by mitochondrial metabolism and by sustaining chemoresistance to a plethora of anticancer drugs. Here, we demonstrate that inhibition of UCP2 triggers Akt/mTOR pathway in a ROS-dependent mechanism in pancreatic adenocarcinoma cells. This event reduces the antiproliferative outcome of UCP2 inhibition by genipin, creating the conditions for the synergistic counteraction of cancer cell growth with the mTOR inhibitor everolimus. Inhibition of pancreatic adenocarcinoma cell growth and induction of apoptosis by genipin and everolimus treatment are functionally related to nuclear translocation of the cytosolic glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The synthetic compound (S)-benzyl-2-amino-2-(S)-3-bromo-4,5-dihydroisoxazol-5-yl-acetate (AXP3009), which binds GAPDH at its redox-sensitive Cys152, restores cell viability affected by the combined treatment with genipin and everolimus, suggesting a role for ROS production in the nuclear translocation of GAPDH. Caspase-mediated apoptosis by genipin and everolimus is further potentiated by the autophagy inhibitor 3-methyladenine revealing a protective role for Beclin1-mediated autophagy induced by the treatment. Mice xenograft of pancreatic adenocarcinoma further confirmed the antiproliferative outcome of drug combination without toxic effects for animals. Tumor masses from mice injected with UCP2 and mTOR inhibitors revealed a strong reduction in tumor volume and number of mitosis associated with a marked GAPDH nuclear positivity. Altogether, these results reveal novel mechanisms through which UCP2 promotes cancer cell proliferation and support the combined inhibition of UCP2 and of Akt/mTOR pathway as a novel therapeutic strategy in the treatment of pancreatic adenocarcinoma.


Interpretation and use of electrical equivalent circuits in studies of epithelial tissues.
Whereas transepithelial and intracellular voltages continue to be measured in renal and other epithelial tissues, the origins of these voltages, especially in renal epithelia, remain obscure. Because epithelial tissues have multiple transcellular and extracellular routes of ion transport, it is convenient to model them with electrical equivalent circuits and, in this way, attempt to understand the relative importance of and relationships between the parallel-series arrangements of the membranes and barriers involved. The interpretation of the equivalent electromotive forces and resistances can be complicated, however, by virtue of nonlinear current-voltage relationships of ionic channels. Thus, for ion transport pathways displaying nonlinear I-V relationships, it is important to distinguish between chord and slope formalisms in the use and interpretation of electrophysiological data. For ions like Na that are generally not at electrochemical equilibrium, the Thévenin electromotive force (emf) of the slope formalism is not synonymous with the Nernst equilibrium potential of the chord formalism nor are the slope and chord conductances equal or constant at all voltages. Thus, it is mandatory that the empirical data be calculated and interpreted in a way consistent with the formalism adopted. The existence of nonlinear behavior, characterized by either Goldman or other types of rectification, exacerbates determination of relative ionic permeabilities, fractional resistances, transference numbers, and other electrophysiological parameters for simple membranes and especially for epithelia. It is argued that the use and interpretation of electrical equivalent circuits of epithelia are not arbitrary but must take into account nonlinearities of the ionic current-voltage relationships and concentration and voltage dependencies of the emfs and conductances.


Ionic mobility in muscle cells.
The diffusivities of ionic potassium, sodium, sulfate, and adenosine triphosphate inside a nmuscle cell are reduced by a factor of 2, relative to diffusivities in aqueous solution. The diffusion coefficients of nonelectrolytes are reduced by the same factor, showing that the diffusion of the ions is retarded by physical, rather than chemical, interactions. In contrast, the diffusivity of the calcium ion, which is taken up by the sarcoplasmic reticulum, is reduced fiftyfold.


Macroeconomic consequences of the COVID-19 pandemic.
We estimate the economic impacts of COVID-19 in the U.S. using a disaster economic consequence analysis framework implemented by a dynamic computable general equilibrium (CGE) model. This facilitates identification of relative influences of several causal factors as "shocks" to the model, including mandatory business closures, disease spread trajectories, behavioral responses, resilience, pent-up demand, and government stimulus packages. The analysis is grounded in primary data on avoidance behavior and healthcare parameters. The decomposition of the influence of various causal factors will help policymakers offset the negative influences and reinforce the positive ones during the remainder of this pandemic and future ones.


Immunisation of rhesus monkeys with Streptococcus mutans, Lactobacillus acidophilus and lipoteichoic acid for protection against dental caries.
An attempt was made to protect rhesus monkeys from dental caries by immunisation with Streptococcus mutans, Lactobacillus acidophilus and lipoteichoic acid (LTA). The vaccine composed of S. mutans gave significant protection against caries, a decrease in the number of S. mutans, an increase in IgG antibodies and a moderate increase in complement-fixing antibodies to LTA. When LTA was used as immunogen, there was only a small reduction in caries, without any detectable antibodies to LTA and a slight increase in IgG antibodies to cell of S. mutans. Vaccines of L. acidophilus or L. fermentum gave no protection. A combined vaccine of S. mutans and L. acidophilus did not reduce the incidence of caries but the antibody titre to cells of S. mutans was raised to a level comparable with that in the S. mutans-immunised monkeys. The results of this investigation in a subhuman primate confirm that immunisation with S. mutans induces protection against caries, unlike the attempt to immunise with two selected strains of lactobacilli. More studies are required to establish the role of specific serotypes of lactobacilli in the development of dental caries.


[Mathematical analysis of several parameters of the microcirculatory bed of muscles and muscular organs].
The authors propose a complex mathematical method for analysis of the microcirculatory link of the vascular bed of muscles and muscular organs. On the basis of the data of the amount and diameters of the vessels the method permits calculating the following parameters according to the proposed pattern of the table-report and formulas: 1. the square surface of the cross-section of the vascular bed; 2. the square surface of the exchange or contact with the tissue surface of the vascular bed; 3. the density of the vascular network in percentage; 4. the blood volume in the vascular bed in volumetric units and average data; 5. the blood volume in one vessel on the average; 6. the volume of the tissue fed by one vessel; 7. the volume of blood per a unit of the surface of the vascular wall.


Cognitive effects of lamotrigine compared with topiramate in patients with epilepsy.
To compare the cognitive effects of lamotrigine vs topiramate as adjunctive therapy in adults with epilepsy. A multicenter, double-blind, randomized, prospective study was conducted in adults with partial seizures. Lamotrigine or topiramate was introduced as an adjunctive therapy to carbamazepine or phenytoin and titrated over 8 weeks to target doses. These drugs were maintained another 8 weeks (maintenance phase) without dosage changes. The primary endpoint was change from screening to the end of the maintenance phase in a combined analysis of standardized measures of cognition (Controlled Oral Word Association Task [COWA]; Stroop Color-Word Interference; Digit Cancellation; Lafayette Grooved Pegboard, dominant hand; Rey Auditory Verbal Learning Test, delayed recall; and Symbol-Digit Modalities test). For the primary endpoint, cognitive performance at the end of the maintenance phase was better with lamotrigine than with topiramate (415.3 vs 315.1; p < 0.001). On the individual cognitive tests, performance was better with lamotrigine than with topiramate in mean changes from screening on the COWA (p < 0.001), Stroop Color-Word Interference (p = 0.038), and Symbol-Digit Modalities tests (p < 0.001). The treatment effect exceeded the minimum clinically important difference for the COWA and the Symbol-Digit Modalities test. Mean changes from screening in the Performance-On-Line test simulating driving skills reflected better performance with lamotrigine than with topiramate (p = 0.021). The median percentage change from baseline in seizure frequency was lower with lamotrigine than with topiramate during the escalation phase (-80% vs -100%; p = 0.028) but not during the maintenance phase (-75% vs -100%; p = 0.062). The frequencies of cognitive adverse events and of premature withdrawals related to cognitive decline were higher with topiramate than with lamotrigine (6% vs 0%; p = 0.013). Lamotrigine had significantly less impact than topiramate on measures of cognition when used as adjunctive therapy for partial seizures.


[Myosin head swivel in a muscular contraction model based on an hypothesis on the role of hydrogen bond excitation].
A theory of muscle contraction developed by the authors in their earlier papers based on the idea of hydrogen-bond attractive force increase under excitation is modified for the model of myosin head swivel. The hydrogen bonds are supposed to be located at a hinge or near actin-myosin contact. The energy of ATP decay is transferred to the hydrogen bonds whose operation results in myosin head swivel. Equation of actin-chain globules vibrations is considered together with the equation for myosin head swivel by an angle psi approximately pi/4. Solution of the set of equations gives the time dependence of a globule displacement and of the force acting on the transverse z-membrane of the muscle fibre. Here the force and displacement in one act of ATP decay are obtained to be of the correct order of magnitude, F approximately 13 kg per 1 cm2 of muscle section and delta 1-10(-6) cm.


PTMA, a new identified autoantigen for oral submucous fibrosis, regulates oral submucous fibroblast proliferation and extracellular matrix.
Oral submucous fibrosis (OSF) is a chronic, insidious disease. The presence of autoantibodies in sera of OSF patients is the most characteristic and direct evidence of OSF being an autoimmune disease. To identify the specific autoantigens which could contribute to antibody production, the Human Proteome Microarrays composed of 19000 full-length unique proteins were employed. 45 proteins correlated with OSF were identified. To validate these results, we used ELISA to validate 28 OSF-associated autoantigens in extended samples. 8 autoantigens were positive in OSF serum with high frequency compared to the healthy controls. Moreover, the mRNA expression of 8 candidates was up-regulated in OSF oral submucous tissues; among them, the protein level of PTMA, the one with the highest positive frequency, was also increased. Through searching the Bioinformatics Public Database and performing the Spearman's rank correlation analysis, we observed that PTMA was positively correlated with fibrosis-related TGFβ1 and SMAD4, the downstream gene of TGFβ1. In TGFβ1-induced fibrosis model of primary human oral submucous fibroblast, PTMA knockdown reversed TGFβ1-induced fibrosis process through inhibiting the cell viability and proliferation of fibroblast, reducing the protein levels of PTMA, Collagen I, α-SMA and MMP9 and increasing the protein levels of SMAD4. In contrast, PTMA overexpression enhanced TGFβ1-induced fibrosis process. Taken together, PTMA is involved in TGFβ1-induced fibrosis in the primary human submucous fibroblast by regulating the expression of ECM-related markers and the downstream genes of TGFβ1. In conclusion, PTMA presents an essential autoantigen during OSF process; targeting PTMA might be a promising strategy for OSF treatment.


The influence of implant design on periprosthetic bone remodelling of two types of uncemented HA-coated hip stems. A two-year follow-up study using DEXA.
Proximal bone resorption and an increased fracture rate in the ABG-I stem has been shown. For these reasons the ABG-I stem design was changed to the ABG-II. In this study periprosthetic bone loss around the ABG-I vs ABG-II is compared to verify if the design changes resulted in improved proximal bone preservation. 51 patients were randomised to either the ABG-I or ABG-II hip prosthesis. Periprosthetic BMD change at various time points was measured using DEXA. Between the two groups (age, gender, weight etc.) no statistical difference was encountered. Compared to the baseline at two years the ABG-II preserved bone better proximally (e.g. zone 7: ABG-II: -3.7%, ABG-I: -11.9%, p=0.05) than the ABG-I. Distally, the trend was opposite and less bone loss was measured for the ABG-I than the ABG-II in zones 3, 4 and 5 (n.s.). this study confirms the philosophy behind the design changes from the ABG-I to ABG-II stem where increased elasticity, more proximal HA-coating, a shorter and distally polished stem, were meant to reduce proximal bone resorption. In future this may lead to fewer periprosthetic fractures and to less complicated revision surgery.


Treponema spp. spirochetes and keratinopathogenic fungi isolated from keratomas in donkeys.
Keratoma is an aberrant keratin mass thought to originate from epidermal horn-producing cells interposed between the stratum medium of the hoof wall and the underlying third phalanx. The cause is unknown, although the presence of keratomas is frequently associated with chronic irritation, focal infection, or trauma. A total of 167 donkeys with keratomas were presented in this study. The diagnosis of a keratoma was based on clinical signs, radiography, and histopathologic examination. Surgical excision was attempted on all donkeys with lameness unless euthanasia was advised. Histopathologic examination, including Giemsa, periodic acid Schiff, and Young's silver special histochemical stains, was performed and showed the presence of fungal hyphae and spirochete bacteria within the degenerate keratin. Polymerase chain reaction (PCR) for treponeme bacteria was performed on 10 keratoma lesions and 9 healthy pieces of hoof (controls). All healthy donkey tissues were negative for the 3 recognized digital dermatitis (DD) treponeme phylogroups, whereas 3 of 10 (30%) donkey keratoma samples were positive for one of the DD treponeme phylogroups. Routine fungal culture and PCR for fungi were performed on 8 keratoma lesions and 8 healthy pieces of hoof (controls). Keratinopathogenic fungi were detected in 1 of 8 (12.5%) keratomas, while only non-keratinopathogenic, environmental fungi were detected in 8 control healthy hoof samples. This is the first time the DD treponemes phylogroup and keratinopathogenic fungi have been detected in keratomas. Further studies are required to assess the significance of this finding.


The ability of a behaviour-specific patient questionnaire to identify poorly performing doctors.
Doctors' ability to communicate with patients varies. Patient questionnaires are often used to assess doctors' communication skills. To investigate whether the Four Habits Patient Questionnaire (4HPQ) can be used to assess the different skill levels of doctors. A cross-sectional study of 497 hospital encounters with 71 doctors. Encounters were videotaped and patients completed three post-visit questionnaires. A 500-bed general teaching hospital in Norway. The proportion of video-observed between-doctor variance that could be predicted by 4HPQ. There were strong correlations between all patient-reported outcomes (range 0.71-0.80 at the doctor level, p < 0.01). 4HPQ correlated significantly with video-observed behaviour at the doctor level (Pearson's r = 0.42, p<0.01) and the encounter level (Pearson's r = 0.27, p < 0.01). The proportion of between-doctor variance not detectable by 4HPQ was 88%. The reason for this discordance was large within-doctor between-encounter variance observed in the videos, and small between-patient variance in patient reports. The maximum positive predictive value for the identification of poorly performing doctors (92%) was achieved with a cut-off score for 4HPQ of 82% (ie, patient assessments were concordant with expert observers for these doctors). Using a patient-reported questionnaire of doctors' communication skills, favourable assessments of doctors by patients were mostly discordant with the views of expert observers. Only very poor performance identified by patients was in agreement with the views of expert observers. The results suggest that patient reports alone may not be sufficient to identify all doctors whose communication skills need improvement training.


Association of prenatal exposure to PM2.5 and NO2 with gestational diabetes in Western New York.
Although many studies have examined the association between prenatal air pollution exposure and gestational diabetes (GDM), the relevant exposure windows remain inconclusive. We aim to examine the association between preconception and trimester-specific exposure to PM2.5 and NO2 and GDM risk and explore modifying effects of maternal age, pre-pregnancy body mass index (BMI), smoking, exercise during pregnancy, race and ethnicity, and neighborhood disadvantage. Analyses included 192,508 birth records of singletons born to women without pre-existing diabetes in Western New York, 2004-2016. Daily PM2.5 and NO2 at 1-km2 grids were estimated from ensemble-based models. We assigned each birth with exposures averaged in preconception and each trimester based on residential zip-codes. We used logistic regression to examine the associations and distributed lag models (DLMs) to explore the sensitive windows by month. Relative excess risk due to interaction (RERI) and multiplicative interaction terms were calculated. GDM was associated with PM2.5 averaged in the first two trimesters (per 2.5 μg/m3: OR = 1.08, 95% CI: 1.01, 1.14) or from preconception to the second trimester (per 2.5 μg/m3: OR = 1.10, 95% CI: 1.03, 1.18). NO2 exposure during each averaging period was associated with GDM risk (per 10 ppb, preconception: OR = 1.10, 95% CI: 1.06, 1.14; first trimester: OR = 1.12, 95% CI: 1.08, 1.16; second trimester: OR = 1.10, 95% CI: 1.06, 1.14). In DLMs, sensitive windows were identified in the 5th and 6th gestational months for PM2.5 and one month before and three months after conception for NO2. Evidence of interaction was identified for pre-pregnancy BMI with PM2.5 (P-for-interaction = 0.023; RERI = 0.21, 95% CI: 0.10, 0.33) and with NO2 (P-for-interaction = 0.164; RERI = 0.16, 95% CI: 0.04, 0.27). PM2.5 and NO2 exposure may increase GDM risk, and sensitive windows may be the late second trimester for PM2.5 and periconception for NO2. Women with higher pre-pregnancy BMI may be more susceptible to exposure effects.


Hypertension treatment in patients with sleep apnea from the European Sleep Apnea Database (ESADA) cohort - towards precision medicine.
We recruited 5,970 hypertensive patients with obstructive sleep apnea (OSA) on current antihypertensive treatment from the European Sleep Apnea Database (ESADA) cohort. The group was subdivided into those receiving monotherapy (n = 3,594) and those receiving dual combined therapy (n = 2,376). We studied how major OSA confounders like age, gender, and body mass index as well as the degree of sleep apnea modified office systolic and diastolic blood pressure. Beta-blockers alone or in combination with a diuretic were compared with other antihypertensive drug classes. Monotherapy with beta-blocker was associated with lower systolic blood pressure, particularly in non-obese middle-aged males with hypertension. Conversely, the combination of a beta-blocker and a diuretic was associated with lower systolic and diastolic blood pressure in hypertensive patients with moderate-severe OSA. Systolic blood pressure was better controlled in female patients using this combined treatment. Our cross-sectional data suggest that specific clinical characteristics and type of antihypertensive medication influence the degree of blood pressure control in hypertensive OSA patients. Controlled trials are warranted.


Preserving 50 Years of Physician Assistant History.
Physician assistants (PAs) have been making history for 50 years. For the past 15 years, the PA History (PAHx) Society has been working to make sure this history is not lost. The Society began in 2002 as a membership organization based at Duke University and since 2011 has been a supporting organization of the National Commission on Certification of Physician Assistants (NCCPA). Highly visible and active in the PA community, the Society encourages all PAs to understand their professional history and embrace it as a part of their professional identity. The Society, through the work of its board of trustees, historians, and staff, tells the story of the collective efforts of physicians, PAs, nurses, lawyers, educators, and policy makers to create a human innovation that has changed how medicine is practiced in the United States and, more recently, in other countries. The Society provides PA faculty and students access to a growing collection of historically relevant and primary source materials that can be used for educational, research, and literary purposes.


Cardiophrenic lymph nodes in liver transplant candidates with hepatocellular carcinoma: imaging characteristics and post-transplant outcomes.
No guidelines exist for the management of cardiophrenic lymph nodes in patients with hepatocellular carcinoma (HCC) being evaluated for liver transplantation. One hundred and seventy-eight patients with HCC listed for liver transplant received both pre-transplant computed tomography (CT) and follow-up CT scans. Enlarged cardiophrenic lymph nodes on CT were characterized and followed on subsequent scans; lymph node outcomes were assigned to "reduced" and "not reduced" categories. Tumor and patient characteristics were also recorded. Seventy-one of one hundred and seventy-eight patients (39.9%) had at least one cardiophrenic lymph node larger than 8 mm in diameter on pre-transplant CT. One hundred and sixty-six total lymph nodes were characterized. Six lymph nodes (3.6%) in two patients increased in size on follow-up imaging; all six cardiophrenic lymph nodes were presumed to represent metastases. There was a statistically significant reduction in lymph node size in patients who were transplanted vs. those who were not transplanted. Furthermore, a statistically significant association was found between increasing Model for End-Stage Liver Disease score and lymph node size reduction. There were no significant differences in post-transplant survival between patients with different lymph node outcomes. In the absence of metastatic disease in other sites, these lymph nodes are probably reactive; further workup is likely not necessary.


A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability.
Proteomics based approaches are emerging as useful tools to identify the targets of bioactive compounds and elucidate their molecular mechanisms of action. Here, we applied a chemical proteomic strategy to identify the peroxisome proliferator-activated receptor γ (PPARγ) as a molecular target of the pro-apoptotic agent 15-ketoatractyligenin methyl ester (compound 1). We demonstrated that compound 1 interacts with PPARγ, forms a covalent bond with the thiol group of C285 and occupies the sub-pocket between helix H3 and the β-sheet of the ligand-binding domain (LBD) of the receptor by Surface Plasmon Resonance (SPR), mass spectrometry-based studies and docking experiments. 1 displayed partial agonism of PPARγ in cell-based transactivation assays and was found to inhibit the AKT pathway, as well as its downstream targets. Consistently, a selective PPARγ antagonist (GW9662) greatly reduced the anti-proliferative and pro-apoptotic effects of 1, providing the molecular basis of its action. Collectively, we identified 1 as a novel PPARγ partial agonist and elucidated its mode of action, paving the way for therapeutic strategies aimed at tailoring novel PPARγ ligands with reduced undesired harmful side effects.


Dose-responses of seven species of cerambycid beetles to synthesized pheromones in field experiments.
Adult male cerambycid beetles of the subfamilies Cerambycinae and Lamiinae emit aggregation-sex pheromones that attract both sexes, and these chemicals can be utilized for quarantine surveillance for related exotic species which produce the same or similar pheromones. Here, we assess how attraction of 7 cerambycid species to pheromone-baited traps was influenced by the release rates of synthesized pheromones from polyethylene sachet emitters. Compounds tested included racemic 3-hydroxyhexan-2-one, the (R)-enantiomer of which is the sole or major pheromone component of numerous cerambycine species, and 2 compounds that are pheromone components of many lamiine species: (E)-6,10-dimethyl-5,9-undecadien-2-yl acetate (fuscumol acetate) and 6-methylhept-5-en-2-ol (sulcatol). We confirmed release rates of these compounds could be manipulated by varying the doses loaded into emitters. Various doses and concentrations, ranging from very dilute to the neat compounds, were then tested in field trials. Several species were most strongly attracted to the highest dose of a tested compound, one species to an intermediate dose, while another species was equally attracted regardless of dose. Our results demonstrate the importance of characterizing dose-response relationships for cerambycid species targeted by pheromone-based trapping.


Screening and diagnosis for colorectal cancer: present and future.
Colon cancer is the third most common cause of cancer diagnosed in the United States, and the second leading cause of cancer death. Although rates of the disease have been going down in recent years, results can be further improved. About 90% of people whose colon cancer is caught before it has spread to nearby lymph nodes or organs survive more than 5 years after diagnosis. However, only 10% of patients whose cancer has spread to distant parts of the body survive 5 years. Diagnosis at an early stage aims to reduce the incidence of tumors in an advanced stage and hence mortality. We analyzed the literature to understand what new tests to use and new directions to take. There is evidence to support the screening of average-risk individuals over the age of 50 years to detect and prevent colon cancer. Screening of these people can only reduce mortality rates, not incidence, identifying cancer at an early stage and through the removal of clinically significant adenomas. Patient preferences and availability of resources play an important role in the selection of screening tests, because each test presents specific risks and specific benefits. The American Cancer Society has added two new screening methods, CT colonography, also known as virtual colonoscopy, and stool DNA tests to the list of options. A small revolution in screening for colon cancer is in the making. The availability of these less invasive tests should increase the number of people who undergo regular screening.


Forum on the future of academic medicine: session III--getting from here to there.
Participants at the third meeting of the AAMC's Forum on the Future of Academic Medicine in June 1997 were asked to give their views of what the main characteristics of successful medical schools should be in the year 2010, given that market pressures are becoming increasingly dominant in the health care environment. The most-cited characteristics concerned structure and management systems. Participants were then asked how far along they thought schools had come in acquiring these and other characteristics they had named. There was wide disagreement on this question, but general consensus that a major obstacle to change at most schools is that faculty do not feel a sense of crisis and thus are not motivated to change. A recurring question at all three forum meetings was whether academic medical centers (i.e., medical schools and their associated teaching hospitals) have an obligation to serve the poor in the future health care system where cross-subsidies will have diminished. Some participants said that service to the poor should be financed through some explicit state-federal mechanism. Others agreed, and added that the treatment of the poor is a valuable educational tool. Dr. Cohen, president of the AAMC, updated the forum on the progress of an AAMC effort to improve the capacity of medical schools to understand their financial status. Another topic was how the AAMC can assist its members through the difficult period of change that market imperatives have created. A guest, Nicholas J. DeGrazia, PhD, a former academic administrator and now a specialist at helping troubled private companies, addressed the forum about the conditions that make change happen in organizations and noted that in academic medicine, there is not a sufficiently concise sense of dissatisfaction to spark meaningful change. He also discussed the characteristics of a successful change agent. Dr. Cohen suggested that perhaps the AAMC could organize a seminar on how to prepare change agents in medical schools. As in the two previous meetings, discussions were wide-ranging and candid, and there was a sense that forum members and others should find ways to have similar types of exchanges with their faculties, administrators, and students because time is of the essence as the market marches on.


Genetic manipulation of Saccharomyces cerevisiae by use of the LYS2 gene.
The structural gene for alpha-aminoadipate reductase (LYS2) was isolated from a Saccharomyces cerevisiae genomic DNA library by complementation of a lys2 mutant. Both genetic and biochemical criteria confirmed that the DNA obtained corresponds to the LYS2 locus on chromosome II. Subcloning and deletion analysis showed that a functional LYS2 gene is contained within a 4.6-kilobase (kb) EcoRI-HindIII fragment of the original insert, and the slightly larger EcoRI-ClaI segment (4.8 kb) was used to construct a series of cloning vehicles, including integrating, episomal, replicative, and centromeric vectors. The cloned DNA was also used to generate a genomic deletion that lacks all LYS2 coding sequences on chromosome II. The level of the LYS2 transcript (4.2 kb) was 10-fold higher in cells grown on minimal medium than in cells grown on complete medium and was not repressed by the presence of lysine alone. Gene disruption, gene replacement, and promoter analysis of the major alpha-factor structural gene (MF alpha 1) were performed to illustrate the utility of the LYS2 gene for the genetic manipulation of yeasts. Because all fungi synthesize lysine via the alpha-aminoadipate pathway, the techniques developed here for using the S. cerevisiae LYS2 gene should be directly applicable to other fungal systems.


Interaction between interferon-stimulated gene 56 and melanoma differentiation-associated gene 5 in Toll-like receptor 3 signaling in normal human mesangial cells.
Toll-like receptor 3 (TLR3) is a pathogen recognition receptor against viral double-stranded RNA. TLR3 signaling is important in antiviral responses, but inappropriate TLR3 signaling may be related with inflammatory renal diseases. Interferon (IFN)-stimulated gene 56 (ISG56) is an IFN-inducible gene that encodes a multifunctional protein with 6 tetratricopeptide motifs and is thought to be involved in antiviral reactions, but the role of ISG56 in TLR3 signaling in mesangial cells is not known well. Normal human mesangial cells were cultured and treated with a synthetic TLR3 ligand polyinosinic-polycytidylic acid, and the expression of ISG56 was analyzed using real-time RT-PCR and Western blot analyses. Using an RNA-interfering technique, involvement of TLR3, IFN-β, melanoma differentiation-associated gene 5 (MDA5) or retinoic acid-inducible gene-I (RIG-I) in ISG56 expression, and of ISG56 in the expression of MDA5, RIG-I, CXCL10 and CCL5 was examined. Treatment of cells with polyinosinic-polycytidylic acid induced ISG56. ISG56 induction was inhibited by knockdown of TLR3 or IFN-β, and knockdown of ISG56 resulted in the decreased expression of MDA5, RIG-I, CXCL10 and CCL5. RNA interference against MDA5 decreased ISG56 expression. ISG56 was induced by TLR3 signaling via newly synthesized IFN-β. ISG56 is involved in the expression of MDA5, RIG-I, CXCL10 and CCL5, and ISG56 and MDA5 may constitute a positive-feedback loop. ISG56 may play a role in immune and inflammatory reactions induced by TLR3 signaling in human mesangial cells.


Reduced Rank Mixed Effects Models for Spatially Correlated Hierarchical Functional Data.
Hierarchical functional data are widely seen in complex studies where sub-units are nested within units, which in turn are nested within treatment groups. We propose a general framework of functional mixed effects model for such data: within unit and within sub-unit variations are modeled through two separate sets of principal components; the sub-unit level functions are allowed to be correlated. Penalized splines are used to model both the mean functions and the principal components functions, where roughness penalties are used to regularize the spline fit. An EM algorithm is developed to fit the model, while the specific covariance structure of the model is utilized for computational efficiency to avoid storage and inversion of large matrices. Our dimension reduction with principal components provides an effective solution to the difficult tasks of modeling the covariance kernel of a random function and modeling the correlation between functions. The proposed methodology is illustrated using simulations and an empirical data set from a colon carcinogenesis study. Supplemental materials are available online.


What do we think about them and what do they think about us? Social representations of interprofessional and interorganizational collaboration in the welfare sector.
Professionals in healthcare, social services, and schools often collaborate when addressing children and adolescents with complex psychosocial needs. Based on theory of social representations, we investigated how professionals in the mentioned organizations perceived each other through their experiences of collaboration. Twenty-nine unit managers and 35 staff members were interviewed in 12 focus groups, and the data collected were subjected to content analysis. Most social representations indicated complex and problematic interprofessional collaboration, although some were positive in nature. We also found social representations regarding ignorance of each other's organizations, distrust, unavailability, and uncommunicativeness. Conceptions of the other party's way of thinking appeared to include adverse attitudes and low expectations from the other side. Concurrently, there was mutual understanding of the limited room to maneuver and heavy workloads. The professionals' perceptions reflected frustration and ambivalence, and also indicated that dialogue was prevented by established boundaries and low expectations. We conclude that arenas are needed for productive dialogue and exchange of relevant knowledge in such collaborative systems, and that management should enable staff to collaborate based on the existing boundaries.


Cutting edge: Discrete functions of mTOR signaling in invariant NKT cell development and NKT17 fate decision.
Invariant NKT (iNKT) cells recently were classified into NKT1, NKT2, and NKT17 lineages with distinct transcription factor and cytokine profiles, but the mechanisms underlying such fate decisions remain elusive. In this article, we report crucial roles for mechanistic target of rapamycin (mTOR) signaling, especially mTORC2, in iNKT cell development and fate determination of NKT17 cells. Loss of Rictor, an obligatory component of mTORC2, decreased thymic and peripheral iNKT cells, which was associated with defective survival. Strikingly, Rictor deficiency selectively abolished the NKT17 lineage, as indicated by a marked reduction in RORγt and IL-17 expression. Moreover, deletion of phosphatase and tensin homolog (Pten) upregulated mTORC2 activity and enhanced NKT17 generation, but concomitant loss of Rictor reversed the NKT17 dysregulation. In contrast, mTORC1 regulators Raptor and Rheb are dispensable for NKT17 differentiation, despite their importance in iNKT cell thymic development. Our findings establish pivotal and unique roles for mTORC2 signaling, which is reciprocally regulated by Rictor and Pten, in NKT17 lineage determination.


Non-occupational post-exposure prophylaxis in Victoria, Australia: responding to high rates of re-presentation and low rates of follow-up.
In Australia, the non-occupational post-exposure prophylaxis service in Victoria (VNPEPS) maintains a database of non-occupational post-exposure prophylaxis (NPEP) use throughout the state. Through the database the service can monitor and respond to patterns of NPEP presentation, re-presentation and follow-up as well as those who test positive for HIV. We describe a cohort of NPEP individuals from the commencement of the service to 31 December 2009. During this time, 1864 individuals presented for NPEP on 2396 occasions. The majority (85%) were men who have sex with men (MSM) presenting after receptive anal intercourse (56.1%). Repeat NPEP presentations were high (17.5%) and follow-up testing at week 12 post-NPEP was low (34%). Twenty-two patients (1.2%) tested positive for HIV at baseline presentation and six patients seroconverted to HIV during follow-up. The VNPEPS has initiated strategies to encourage behaviour change for those who re-present for NPEP, and to improve rates of week 12 follow-up.


Activation of Wnt/beta-catenin/Tcf signaling in mouse skin carcinogenesis.
Although Wnt/beta-catenin/Tcf signaling pathway has been shown to be an important factor in the development of many malignancies including colorectal, ovarian, prostate, and many other cancers, little is known about its role in non-melanoma skin cancers. Here, we report the first evidence that beta-catenin/Tcf signaling pathway is constitutively activated in non-melanocytic skin tumors induced by two stage chemical carcinogenesis protocol. Mouse skin tumors showed cytoplasmic and nuclear accumulation of beta-catenin, and upregulation of beta-catenin/Tcf target genes (c-myc and c-jun). We found high levels of skin-expressed Wnt proteins (Wnt 3, 4, and 10b) in different parts of the tumors, likely representing key upstream events in beta-catenin/Tcf activation during mouse skin carcinogenesis. Inhibition of beta-catenin/Tcf signaling by ectopic expression of dominant negative Tcf4 resulted in significant inhibition of growth in squamous cell carcinoma cells. A role of the constitutive activation of beta-catenin/Tcf signaling in skin carcinogenesis is discussed.


Intact parathyroid hormone: performance and clinical utility of an automated assay based on high-performance immunoaffinity chromatography and chemiluminescence detection.
The performance and clinical utility of an automated assay of intact parathyroid hormone (parathyrin, PTH) are evaluated. The method is based on the extraction of PTH from plasma by an HPLC column containing immobilized anti-(44-68 PTH) antibodies. The PTH retained is detected with a postcolumn reactor and use of anti-(1-34 PTH) chemiluminescent-labeled antibodies. The total cycle time of the assay is 6.5 min per injection after a 1-h incubation. The lower limit of detection for PTH in a 66-microL plasma sample was 0.5 pmol/L based on peak heights and 0.2 pmol/L based on peak areas. Mean analytical recovery for PTH added to plasma was 97%. The within-day precisions (CVs) for 4.2 and 30 pmol/L PTH plasma samples were 9.2% and 5.6% and the day-to-day precisions were 10.3% and 5.7%, respectively. No significant interferences from 1-34, 44-68, or 53-84 PTH fragments were noted, even at highly increased concentrations of fragments. The correlation of results with those of a manual assay of intact PTH was 0.97, and the results showed good agreement with disease state for patients with hypo- or hyperparathyroidism. The specificity of the assay for primary hyperparathyroidism was greater than 95%. We discuss the advantages (speed and quality control) of this approach over current immunoassays and the potential use of this method for detecting other analytes.


Immunogenicity of Borrelia burgdorferi arthritis-related protein.
Immunization against arthritis-related protein (Arp) elicits antibody in mice that resolves arthritis but is not protective against challenge with Borrelia burgdorferi. In mice immunized against Arp, an unrelated 37-kDa protein (P37-42), outer surface protein A (OspA), or glutathione S-transferase (GT) and then challenged by syringe or tick, only OspA conferred protection. Passive transfer of Arp antiserum into infected SCID mice induced arthritis resolution, but antisera to P37-42, OspA, GT, or six overlapping Arp peptide fragments did not. Results suggest that the arthritis-resolving immunogenicity is specific to Arp, but the relevant epitopes may be conformational.


Resistance training in humans and mechanical overload in rodents do not elevate muscle protein lactylation.
Although several reports have hypothesized that exercise may increase skeletal muscle protein lactylation, empirical evidence in humans is lacking. Thus, we adopted a multi-faceted approach to examine if acute and subchronic resistance training (RT) altered skeletal muscle protein lactylation levels. In mice, we also sought to examine if surgical ablation-induced plantaris hypertrophy coincided with increases in muscle protein lactylation. To examine acute responses, participants' blood lactate concentrations were assessed before, during, and after eight sets of an exhaustive lower body RT bout (n = 10 trained college-aged men). Vastus lateralis biopsies were also taken before, 3-h post, and 6-h post-exercise to assess muscle protein lactylation. To identify training responses, another cohort of trained college-aged men (n = 14) partook in 6 weeks of lower-body RT (3x/week) and biopsies were obtained before and following the intervention. Five-month-old C57BL/6 mice were subjected to 10 days of plantaris overload (OV, n = 8) or served as age-matched sham surgery controls (Sham, n = 8). Although acute resistance training significantly increased blood lactate responses ∼7.2-fold (p < 0.001), cytoplasmic and nuclear protein lactylation levels were not significantly altered at the post-exercise time points, and no putative lactylation-dependent mRNA was altered following exercise. Six weeks of RT did not alter cytoplasmic protein lactylation (p = 0.800) despite significantly increasing VL muscle size (+3.5%, p = 0.037), and again, no putative lactylation-dependent mRNA was significantly affected by training. Plantaris muscles were larger in OV versus Sham mice (+43.7%, p < 0.001). However, cytoplasmic protein lactylation was similar between groups (p = 0.369), and nuclear protein lactylation was significantly lower in OV versus Sham mice (p < 0.001). The current null findings, along with other recent null findings in the literature, challenge the thesis that lactate has an appreciable role in promoting skeletal muscle hypertrophy.


Psychological Intervention and COVID-19: What We Know So Far and What We Can Do.
The coronavirus COVID-19 and the global pandemic has already had a substantial disruptive impact on society, posing major challenges to the provision of mental health services in a time of crisis, and carrying the spectre of an increased burden to mental health, both in terms of existing psychiatric disorder, and emerging psychological distress from the pandemic. In this paper we provide a framework for understanding the key challenges for psychologically informed mental health care during and beyond the pandemic. We identify three groups that can benefit from psychological approaches to mental health, and/or interventions relating to COVID-19. These are (i) healthcare workers engaged in frontline response to the pandemic and their patients; (ii) individuals who will experience the emergence of new mental health distress as a function of being diagnosed with COVID-19, or losing family and loved ones to the illness, or the psychological effects of prolonged social distancing; and (iii) individuals with existing mental health conditions who are either diagnosed with COVID-19 or whose experience of social distancing exacerbates existing vulnerabilities. Drawing on existing literature and our own experience of adapting treatments to the crisis we suggest a number of salient points to consider in identifying risks and offering support to all three groups. We also offer a number of practical and technical considerations for working psychotherapeutically with existing patients where COVID-19 restrictions have forced a move to online or technologically mediated delivery of psychological interventions.


Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores.
YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation.


CR2Cancer: a database for chromatin regulators in human cancer.
Chromatin regulators (CRs) can dynamically modulate chromatin architecture to epigenetically regulate gene expression in response to intrinsic and extrinsic signalling cues. Somatic alterations or misexpression of CRs might reprogram the epigenomic landscape of chromatin, which in turn lead to a wide range of common diseases, notably cancer. Here, we present CR2Cancer, a comprehensive annotation and visualization database for CRs in human cancer constructed by high throughput data analysis and literature mining. We collected and integrated genomic, transcriptomic, proteomic, clinical and functional information for over 400 CRs across multiple cancer types. We also built diverse types of CR-associated relations, including cancer type dependent (CR-target and miRNA-CR) and independent (protein-protein interaction and drug-target) ones. Furthermore, we manually curated around 6000 items of aberrant molecular alterations and interactions of CRs in cancer development from 5007 publications. CR2Cancer provides a user-friendly web interface to conveniently browse, search and download data of interest. We believe that this database would become a valuable resource for cancer epigenetics investigation and potential clinical application. CR2Cancer is freely available at http://cis.hku.hk/CR2Cancer.


Long-term follow-up for childhood cancer survivors: the Geneva experience.
Although the 5-year survival for pediatric cancer in Switzerland today is over 85%, two thirds of the survivors will develop chronic health conditions due to the disease or to the toxicity of treatments. In this context, a long-term personalized follow-up program (LTFU program), was set up at the University Hospitals of Geneva (HUG) since 2015. We aimed to describe this program, more particularly the specialized follow-ups set up, the cumulative burden of the chronic health conditions, and finally assess the satisfaction of patients and/or their parents with it. A monocentric retrospective study was performed where data on follow-ups and chronic health conditions were collected from medical charts of people who had childhood cancer and who participated in the LTFU program. Chronic health conditions were classified and graded in severity with the Common Terminology Criteria of Adverse Events (CTCAE) classification, version 5.0. This study was completed by a satisfaction survey among patients and/or their parents. Out of 83 eligible patients, 51 (61.4%) accepted to participate, with an average age of 17.4 years (range, 10 to 35) at the time of study. Mean delay since end of treatment was 9.8 years (range: 4.5-31). The prevalence of any chronic health condition is 82.3%, 43.1% for having 1 or 2 chronic health conditions and 39.2% for having more than 3 chronic health conditions. The total number of Grade CTCAE 1-4 chronic health conditions was 118 for the 51 participants, with a mean of 2.3 (range, 0 to 7) disorders per patient. The most frequently affected systems were neurological (14.4%), musculoskeletal (13.6%), endocrine (9.3%) and renal (9.3%) systems. Sarcoma, central nervous system tumors and neuroblastoma were the diagnoses associated with the highest average number of chronic health conditions. Among the 118 questionnaires sent to patients and/or parents, we received 82 (69.5%) responses. The level of satisfaction was good to excellent for more than 90% of the participants, for all the items evaluated. Childhood cancer survivors present a significant number of chronic health conditions, confirming the need for appropriate long-term, multidisciplinary and patient-specific medical follow-up based on the primary diagnosis and therapies received. Moreover, the LTFU program at the HUG was highly appreciated by patients and/or their parents and this motivates its permanent conduct.


Processing of human cytomegalovirus envelope glycoproteins in and egress of cytomegalovirus from human astrocytoma cells.
The synthesis of human cytomegalovirus (HCMV) envelope glycoproteins and the production of infectious HCMV in human astrocytoma and skin fibroblast (SF) cells were analysed. HCMV envelope glycoproteins synthesized in astrocytoma cells had lower Mrs than the same glycoproteins synthesized in SF cells regardless of the strain of HCMV used, showing that the differences observed were due to differences in processing by the host cell and not the strain of HCMV used. HCMV envelope glycoproteins synthesized in astrocytoma cells were found to contain less galactosamine. Moreover, when synthesized in SF cells some HCMV glycoproteins contained a protease-resistant fragment owing to the presence of a cluster of O-linked oligosaccharides on the polypeptide. This fragment was not present when these HCMV glycoproteins were synthesized in astrocytoma cells. These data suggested that HCMV glycoproteins synthesized in astrocytoma cells contain fewer O-linked oligosaccharides. In contrast, other post-translational events such as proteolytic cleavage of the HCMV gB glycoprotein and the formation of disulphide-linked complexes did occur. The virus produced in astrocytoma cells was capable of infecting SF cells, suggesting that complete O-glycosylation is not needed to produce infectious HCMV. However, astrocytoma cells were slow to release virus into the culture medium, suggesting that a fully functional Golgi network is needed for efficient egress of HCMV from the host cell.


Performance norms for the VA compact disc versions of CID W-22 (Hirsh) and PB-50 (Rush Hughes) word lists.
The purpose of this study was to establish normative articulation functions for the Hirsh recordings of the CID W-22 word lists and te Rush Hughes recordings of the PB-50 word lists as recorded on the VA compact disc. Twenty-four young adults with normal hearing listened to both sets of materials presented in quiet at 12 levels (0-56 dB HL). Presentation levels on average needed to be 10 dB higher for the PB-50 word lists to obtain word recognition performance scores equal to those for the W-22s. Maximum word recognition scores of 95 to 100 percent were obtained for the W-22s at lower presentation levels (> 40 dB HL), compared to 80 to 90 percent for the PB-50s at the maximum presentation level (56 dB HL). Mean slopes for the W-22 and PB-50 functions were 4.1 percent/dB and 1.9 percent/dB, respectively. Test-retest reliability was judged to be clinically appropriate for both sets of materials. Item analyses revealed a substantially skewed distribution toward easy items for the W-22 word lists compared to a more balanced distribution of item difficulty for the PB-50 lists. List equivalency was also judged to be clinically appropriate for the PB-50 word lists.


Safety and efficacy of an oncolytic viral strategy using bortezomib with ICE/R in relapsed/refractory HIV-positive lymphomas.
HIV-associated lymphomas (HALs) have high rates of latent infection by gammaherpesviruses (GHVs). We hypothesized that proteasome inhibition would induce lytic activation of GHVs and inhibit HIV infectivity via preservation of cytidine deaminase APOBEC3G, improving lymphoma control. We tested this oncolytic and antiviral strategy by using bortezomib combined with ifosfamide, carboplatin, and etoposide (ICE) alone or with rituximab (ICE/R) in relapsed/refractory HAL. A 3+3 dose-escalation design was used with a 7-day lead-in period of single-agent bortezomib. Bortezomib was administered intravenously on days 1 and 8 of each cycle at 1 of 4 dose levels: 0.7, 1.0, 1.3, or 1.5 mg/m2 ICE began day 8 of cycle 1 and day 1 of subsequent cycles. Rituximab was included on day 1 of cycles 2 to 6 for CD20+ lymphomas. Twenty-three patients were enrolled. The maximum tolerated dose of bortezomib was not reached. Grade 4 toxicities attributable to bortezomib were limited to myelosuppression. Responses occurred in 17 (77%) of 22 patients receiving any protocol therapy. The 1-year overall survival was 57%. After bortezomib alone, both patients with Kaposi sarcoma herpesvirus (KSHV)-positive lymphoma had more than a 1-log increase in KSHV viral load. In 12 patients with Epstein-Barr virus (EBV)-positive lymphoma, median values of EBV viral load increased. Undetectable HIV viremia at baseline in the majority of patients limited evaluation of HIV inhibition. APOBEC3G levels increased in 75% of evaluable patients. Bortezomib combined with ICE/R in patients with relapsed/refractory HAL is feasible with response and survival comparing favorably against previously reported second-line therapies. Changes in GHV viral loads and APOBEC3G levels trended as hypothesized. This trial was registered at www.clinicaltrials.gov as #NCT00598169.


Autoantibodies to prothrombin and phosphatidylserine/prothrombin-complexes: do they contribute to the serodiagnosis of primary and secondary anti-phospholipid syndrome?
The diagnostic and clinical relevance of Ab to pure and phosphatidylserine-complexed prothrombin for primary and secondary APS was investigated in a total of 357 patients with (n = 169) and without (n = 188) connective tissue diseases. The overall frequency of anti-prothrombin Ab in sAPS, pAPS and patients without APS-related symptoms were found to be 50.0, 37.5 and 22.0%, respectively. From a total of 72 anti-prothrombin-positive samples, 12.5% were specific for pure prothrombin, 31.9% for phosphatidylserine/prothrombin-complexes and 55.6% recognized both antigenic forms. The simultaneous occurrence of other anti-phospholipid Ab was observed in 84% of all sera. Both types of anti-prothrombin Ab are significantly associated with lupus anticoagulant activity, but only Ab to pure prothrombin display such a relationship to clinical manifestations of APS. Based on these results, it cannot be recommended at present to include anti-prothrombin assays in the routine procedure for the serodiagnosis of APS. However, patients negative for lupus anticoagulant and typical APS-related anti-phospholipid Ab should be tested for anti-prothrombin reactivity, favoring, mainly due to its higher specificity, the ELISA containing pure prothrombin as antigen.


Comprehensive assessment of the quality of commercial cranberry products. Phenolic characterization and in vitro bioactivity.
Cranberry (Vaccinium macrocarpon) products have been widely recommended in traditional American medicine for the treatment of urinary tract infection (UTI). A total of 19 different commercial cranberry products from American and European markets have been analyzed by different global phenolic methods and by UPLC-DAD-ESI-TQ MS. In addition, in vitro antioxidant capacity and uropathogenic bacterial antiadhesion activity tests have been performed. Results revealed that products found in the market widely differed in their phenolic content and distribution, including products completely devoid of flavan-3-ols to highly purified ones, either in A-type proanthocyanidins (PACs) or in anthocyanins. The product presentation form and polyphenolic profile widely affected the antiadhesion activity, ranging from a negative (nulel) effect to a MIC = 0.5 mg/mL for cranberry powders and a MIC=112 mg/mL for gel capsule samples. Only 4 of 19 products would provide the recommended dose of intake of 36 mg total PACs/day. Of most importance was the fact that this dose would actually provide as low as 0.00 and up to 205 μg/g of procyanidin A2, indicating the lack of product standardization and incongruence between global and individual compound analysis.


[Expression of the gene for hybrid beta-lactamase pBR322 with C-terminal fragment containing tuftsin (Thr-Lys-Pro-Arg)].
A hybrid beta-lactamase gene with a synthetic tuftsin-coding DNA fragment inserted at the Pst I-site of pBR322 plasmid has been obtained and its expression has been studied. Radioactive amino acids have been used to show that in E. coli chi 925 minicells up to 30% of newly synthesized chimeric protein is secreted into periplasm providing the tuftsin transport. After hybrid protein cleavage with CNBr, tuftsin has been isolated using ion-exchange and thin-layer chromatography.


Antithrombotic therapy strategies for atrial fibrillation patients undergoing percutaneous coronary intervention: A systematic review and network meta-analysis.
The aim of this systematic review and network meta-analysis was to evaluate the comparative efficacy and safety of antiplatelet agents, vitamin K antagonist (VKA) and non-VKA oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched to identify clinical trials comparing antiplatelet drugs with VKA and NOACs or their combination in AF patients undergoing PCI with a mean/median follow-up of at least 12 months. A network meta-analysis was conducted to directly and indirectly compare the efficacy and safety of competitive antithrombotic regimens with a Bayesian random-effects model. Results were presented as relative risks (RRs) and 95% confidence intervals (CIs). A total of 15 studies enrolling 13,104 patients were included. Among 5 regimens, rivaroxaban 15 mg daily plus P2Y12 inhibitor treatment demonstrated significant superiority over dual- and triple-antiplatelet therapies (DAPT, TT) in reducing thromboembolic events (0.64 [0.38, 0.95] and 0.68 [0.43, 0.98], respectively) but showed the maximum possibility of major bleeding risk, while VKA plus single antiplatelet therapy (SAPT) seemed the safest. Significantly less risk of major bleeding was seen in DAPT group than that in TT group (0.63 [0.39, 0.99]). The present study suggests that combination of VKA and SAPT is the best choice for AF patients undergoing PCI considering both efficacy and safety. Rivaroxaban 2.5 mg twice daily plus DAPT treatment owns the highest probability to be the optimal alternative to VKA plus SAPT for these patients.


Effects of upper-limb exercise on lower-limb cutaneous microvascular function in post-surgical varicose-vein patients.
Regular walking exercise attenuates lower-limb cutaneous microvascular endothelial dysfunction in post-surgical varicose-vein patients. This study assessed the effects of upper-limb exercise training on lower-limb cutaneous microvascular function in this patient group. Six post-surgical (4-5 weeks) varicose-vein patients completed an 8-week arm-crank exercise training programme. Changes in cutaneous microvascular function of the lower leg were assessed using laser Doppler flowmetry and iontophoretic administration of endothelial-dependent and -independent agonists [acetylcholine (ACh) and sodium nitroprusside (SNP), respectively]. At 8 weeks, median lower-limb cutaneous vasodilator responsives to ACh and SNP remained unchanged relative to baseline (e.g. 6 mC: 37 (interquartile range 24-63) vs. 40 (20-71) PU and 35 (23-48) vs. 38 (21-64) PU, respectively for the supine position). Upper-limb exercise appears ineffective for improving lower-limb cutaneous microvascular function in post-surgical varicose-vein patients. Therefore, limb specificity appears an important factor in optimal exercise prescription for these patients.


The investigation of thermal behaviour and physical properties of several types of contemporary gutta-percha points.
To analyse the contents and thermal behaviour of several brands of contemporary gutta-percha points due to the variable nature of the components of gutta-percha, and the impact they can have on the physical properties of this unique material during canal filling. Six brands of gutta-percha were investigated: Conform Fit TM Gutta-Percha Points for ProTaper Gold® (PTG) (Dentsply Sirona), ProTaper® Universal Gutta-Percha Points (PTU) (Dentsply Sirona), Autofit TM Feathered Tip Gutta Percha (Kerr), Mtwo® Gutta-Percha (VDW), Gutta Percha Root Canal Points (GC, GC Corporation) and Gutta-Percha Points ISO Color-Coded (ISO; Dentsply Sirona). The organic and inorganic fractions of gutta-percha points were separated by quantitative chemical analysis. Thermal conductivity was detected using a laser flash method. In addition, the thermal behaviour of gutta-percha in response to temperature variations was analysed using differential scanning calorimetry (DSC). Kruskal-Wallis and Dunn tests were applied for comparisons amongst groups for chemical compositions and temperature obtained from DSC. The associations between compositions and thermal conductivity were determined using simple linear regression. A p value <.05 was considered to be statistically significant. There were significant difference in the inorganic fractions of the gutta-percha points in percentage by weight amongst the groups (p < .05). PTG had the lowest thermal conductivity (0.42 W/m K). A positive correlation was observed between the percentage of inorganic fraction and thermal conductivity (r = 0.95). The initial phase changing temperature and peak temperature measured by DSC were significantly different when the β-form transformed to α-form (p < .05), whereas no significant difference was found during the α-form to the amorphous-phase transition (p > .05). Chemical compositions and initial phase changing temperature by DSC varied according to the various brands of gutta-percha points. Conform Fit TM gutta-percha had the lowest percentage of inorganic fraction and thermal conductivity amongst these six brands of gutta-percha. Thermal conductivity had the strongest positive correlation with the percentage of inorganic components and zinc, whilst there was a negative correlation to the amount (ratio) of gutta-percha.


Dermatobia hominis myiasis among travelers returning from South America.
Dermatobia hominis is the most common cause of myiasis in Central and South America, affecting mammals and humans, causing nonhealing furuncle-like lesions. During the years 1994 to 1999, 14 Israeli travelers returning from South America were diagnosed with D hominis myiasis. The approach consists of correct diagnosis and a proper removal of the larvae, after which the patients heal with no complications.


Neurite guidance by non-neuronal cells in culture: preferential outgrowth of peripheral neurites on glial as compared to nonglial cell surfaces.
Growing axons in the peripheral nervous system (PNS) encounter a variety of cellular and extracellular substrates. Since it is difficult to sort out the possible contributions of these diverse components of the extracellular environment to axonal guidance in vivo, I have developed an in vitro system to study neurite outgrowth on two classes of cells which may provide as substrates for growing axons during development or regeneration: glial cells, e.g., astrocytes and Schwann cells, and nonglial cells, e.g., fibroblasts. Although neurites from sympathetic and spinal sensory ganglia explants grew onto preformed monolayers of both glial and nonglial cells, glial cells were a markedly better substrate. On the glial cells the neurites extended at a rate of 25 to 30 micron/hr and traveled singly or in fine fascicles; their growth cones displayed long filopodia and migrated on the upper surface of the monolayer cells. Conditioned media experiments suggested that neurite outgrowth on glial cell monolayers was not mediated by soluble secreted factors. These results indicate that the glial cell surface is an attractive substrate for neurite outgrowth. In contrast, on nonglial cells the rate of outgrowth was only 10 to 15 micron/hr, large neurite fascicles were common, and the growth cones migrated beneath the monolayer cells in contact with the underlying artificial substrate. This location of the growth cone, coupled with the observation that conditioned medium from these cells promoted neurite outgrowth only when bound to artificial substrates, suggests that secreted substrate-associated components may be an important determinant of neurite outgrowth on nonglial cell monolayers.(ABSTRACT TRUNCATED AT 250 WORDS)


Trypanosoma cruzi in Mexican Neotropical vectors and mammals: wildlife, livestock, pets, and human population.
To provide primary evidence of Trypanosoma cruzi landscape genetics in the Mexican Neotropics. Trypanosoma cruzi and discrete typing units (DTU) prevalence were analyzed in landscape communities of vectors, wildlife, livestock, pets, and sympatric human populations using endpoint PCR and sequencing of all relevant amplicons from mitochondrial (kDNA) and nuclear (ME, 18S, 24Sα) gene markers. Although 98% of the infected sample-set (N=2 963) contained single or mixed infections of DTUI (TcI, 96.2%) and TcVI (22.6%), TcIV and TcII were also identified. Sensitivity of individual markers varied and was dependent on host taxon; kDNA, ME and 18S combined identified 95% of infections. ME genotyped 90% of vector infections, but 60% of mammals (36% wildlife), while neither 18S nor 24Sα typed more than 20% of mammal infections. Available gene fragments to identify or genotype T. cruzi are not universally sensitive for all landscape parasite populations, highlighting important T. cruzi heteroge- neity among mammal reservoir taxa and triatomine species.


Laser absorption spectroscopy measurements of different pulmonary oxygen gas concentrations in transmittance and remittance geometry: phantom study.
The gas in scattering media absorption spectroscopy (GASMAS) technique has the potential for continuous, clinical monitoring of preterm infant lung function, removing the need for X-ray diagnosis and reliance on indirect and relatively slow measurement of blood oxygenation. We aim to determine the optimal source-detector configuration for reliable pathlength calculation and to estimate the oxygen gas concentration inside the lung cavities filled with humidified gas with four different oxygen gas concentrations ranging between 21% and 100%. Anthropomorphic optical phantoms of neonatal thorax with two different geometries were used to acquire GASMAS signals, for 30 source-detector configurations in transmittance and remittance geometry of phantoms in two sizes. The results show that an internal light administration is more likely to provide a high GASMAS signal-to-noise ratio (SNR). In general, better SNRs were obtained with the smaller set of phantoms. The values of pathlength and O2 concentrations calculated with signals from the phantoms with optical properties at 820 nm exhibit higher variations than signals from the phantoms with optical properties at 764 nm. Our study shows that, by moving the source and detector over the thorax, most of the lung volumes can potentially be assessed using the GASMAS technique.


The CNK1 scaffold binds cytohesins and promotes insulin pathway signaling.
Protein scaffolds play an important role in signal transduction, regulating the localization of signaling components and mediating key protein interactions. Here, we report that the major binding partners of the Connector Enhancer of KSR 1 (CNK1) scaffold are members of the cytohesin family of Arf guanine nucleotide exchange factors, and that the CNK1/cytohesin interaction is critical for activation of the PI3K/AKT cascade downstream from insulin and insulin-like growth factor 1 (IGF-1) receptors. We identified a domain located in the C-terminal region of CNK1 that interacts constitutively with the coiled-coil domain of the cytohesins, and found that CNK1 facilitates the membrane recruitment of cytohesin-2 following insulin stimulation. Moreover, through protein depletion and rescue experiments, we found that the CNK1/cytohesin interaction promotes signaling from plasma membrane-bound Arf GTPases to the phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) to generate a PIP(2)-rich microenvironment that is critical for the membrane recruitment of insulin receptor substrate 1 (IRS1) and signal transmission to the PI3K/AKT cascade. These findings identify CNK1 as a new positive regulator of insulin signaling.


Temperature-regulated efflux pump/potassium antiporter system mediates resistance to cationic antimicrobial peptides in Yersinia.
Most bacterial pathogens are resistant to cationic antimicrobial peptides (CAMPs) that are key components of the innate immunity of both vertebrates and invertebrates. In Gram-negative bacteria, the known CAMPs resistance mechanisms involve outer membrane (OM) modifications and specifically those in the lipopolysaccharide (LPS) molecule. Here we report, the characterization of a novel CAMPs resistance mechanism present in Yersinia that is dependent on an efflux pump/potassium antiporter system formed by the RosA and RosB proteins. The RosA/RosB system is activated by a temperature shift to 37 degrees C, but is also induced by the presence of the CAMPs, such as polymyxin B. This is the first report of a CAMPs resistance system that is induced by the presence of CAMPs. It is proposed that the RosA/RosB system protects the bacteria by both acidifying the cytoplasm to prevent the CAMPs action and pumping the CAMPs out of the cell.


FGFR2 gene polymorphisms are associated with breast cancer risk in the Han Chinese population.
Breast cancer is one of the most common neoplasms among women in many developing countries including China, and is the leading cause of female cancer-related deaths worldwide. In the current study, we analyzed the relationship between 14 tag single-nucleotide polymorphisms (tSNPs) and breast cancer risk in the Han Chinese population including 185 breast cancer patients and 199 healthy women controls on the different types of breast cancer and menopausal status. Overall, we found rs2981579 in the FGFR2 gene, and rs2380205 were associated with breast cancer susceptibility. These findings indicate that FGFR2 was associated with breast cancer risk in the Han Chinese population, support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations.


Cowpea bruchid midgut transcriptome response to a soybean cystatin--costs and benefits of counter-defence.
The insect digestive system is the first line of defence protecting cells and tissues of the body from a broad spectrum of toxins and antinutritional factors in its food. To gain insight into the nature and breadth of genes involved in adaptation to dietary challenge, a collection of 20 352 cDNAs was prepared from the midgut tissue of cowpea bruchid larvae (Callosobruchus maculatus) fed on regular diet and diets containing antinutritional compounds. Transcript responses of the larvae to dietary soybean cystatin (scN) were analysed using cDNA microarrays, followed by quantitative real-time PCR (RT-PCR) confirmation with selected genes. The midgut transcript profile of insects fed a sustained sublethal scN dose over the larval life was compared with that of insects treated with an acute high dose of scN for 24 h. A total of 1756 scN-responsive cDNAs was sequenced; these clustered into 967 contigs, of which 653 were singletons. Many contigs (451) did not show homology with known genes, or had homology only with genes of unknown function in a Blast search. The identified differentially regulated sequences encoded proteins presumptively involved in metabolism, structure, development, signalling, defence and stress response. Expression patterns of some scN-responsive genes were consistent in each larval stage, whereas others exhibited developmental stage-specificity. Acute (24 h), high level exposure to dietary scN caused altered expression of a set of genes partially overlapping with the transcript profile seen under chronic lower level exposure. Protein and carbohydrate hydrolases were generally up-regulated by scN whereas structural, defence and stress-related genes were largely down-regulated. These results show that insects actively mobilize genomic resources in the alimentary tract to mitigate the impact of a digestive protease inhibitor. The enhanced or restored digestibility that may result is possibly crucial for insect survival, yet may be bought at the cost of weakened response to other stresses.


Incision length correlates with patient weight, height, and gender when using a minimal-incision technique in total hip arthroplasty.
Minimal-incision technique in total hip arthroplasty (THA) has been previously defined as requiring an incision of 10 cm or less. A higher complication rate for overweight or muscular patients has been demonstrated when this arbitrary cutoff is used. The purpose of this study was to perform minimal-incision technique surgery without a specific incision length cutoff on a cohort of nonselected, consecutive THA patients to determine if patient height, weight, body mass index, gender, type of femoral fixation, and/or age correlated with incision length. A total of 115 patients underwent THA (posterior approach) using minimal-incision technique by a single, experienced surgeon who performed the smallest incision that was feasible. There was a significant correlation between incision size and patient weight (p < .0001)), height (p = .007), and gender (p = .04). Complications included one patient each with postoperative instability, an intraoperative calcar fracture, and an intraoperative distal incision skin tear. These findings demonstrate that larger patients can expect a longer incision with this technique, and that for a given weight, women will have longer incisions than men. Selecting appropriate incision length for minimally invasive THA reduces potential associated complications.


Physiological parameters of Bacillus cereus marking the end of acid-induced lag phases.
During lag phases microbial cells adapt to their environment and prepare to proliferate. Physiological parameters of B. cereus cells upon exposure to near-growth-boundary acid stress were investigated and markers for the transition between lag phase and growth were identified using fluorescent probes combined with flow cytometry. Determination of cell counts and optical density revealed lag phases of 1h, 2h and 5h, in cultures shifted to pH 7, pH 5.3 (set with lactic acid) and pH 4.9 (set with sulfuric acid), respectively. The obtained lag phases fitted the trends in ATP levels, which were constant during the lag phase and increased after the onset of growth. Both the percentage of PI-stained cells and cells with a significant membrane potential decreased during the lag phase. This points to repair of membrane damage and the loss of membrane potential. However, both trends extended in the growth phase, thus not suitable to mark the onset of growth. The activity of the electron transfer chain and esterases did allow for assessment of transition between lag and growth phase. These activities were generally low during the lag phase and increased after the onset of growth. Our results show that, independent of the duration of the lag phase, for different conditions the same physiological trends could be observed. The change in signal of selected probes can be used as a marker for transition from lag phase to the growth phase and may aid in identification of novel targets interfering with bacterial exit from lag phase.


Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species.
The p53-dependent initiation of apoptosis is accompanied by the induction of proline oxidase (POX), a mitochondrial enzyme catalyzing the conversion of proline to pyrroline-5-carboxylate with the concomitant transfer of electrons to cytochrome c. However, the contribution of increased POX activity to apoptosis, if any, remains unknown. Using Adriamycin to initiate p53-dependent apoptosis, we showed that the expression of POX is up-regulated in a time- and dose-dependent manner in a human colon cancer cell line (LoVo). In cells expressing POX, the addition of proline increases reactive oxygen species (ROS) generation in a concentration-dependent manner; glutamate, a downstream product of proline oxidation, had no effect. Induction of POX was dependent on the p53 status of the cell. In the conditionally immortalized murine colonic epithelial cell line YAMC, where the p53 phenotype can be modulated by temperature, proline oxidase expression and ROS production could only be induced when the cells were phenotypically p53-positive. To confirm that the observed ROS production was not secondary to some other effect of p53, we also conditionally expressed POX in a p53-negative colon cancer line. Again, we found a proline-dependent ROS increase with POX expression. We hypothesize that proline oxidation supports the generation of ROS by donating reducing potential to an electron transport chain altered either by p53-dependent mechanisms or by overexpression of POX.


Evaluation of safety and efficacy profile of Nigella sativa oil as an add-on therapy, in addition to alpha-keto analogue of essential amino acids in patients with chronic kidney disease.
Chronic kidney disease (CKD) encompasses a spectrum of different pathophysio- logic processes associated with abnormal kidney function. When it reaches end-stage renal disease (ESRD), the only option is dialysis and renal transplantation. This is unaffordable by most patients. Hence, newer treatment modalities are being looked for, which can slow down the progression of CKD and delay the development of ESRD. This study aimed to evaluate the efficacy and safety of Nigella sativa oil as an add-on therapy in addition to alpha-keto analogue of essential amino acids in patients with CKD Stages 3 and 4. The study was conducted at a tertiary care center in North India on patients with CKD Stages 3 and 4. It was a prospective, comparative, and open-labeled study. One hundred and fifty patients were enrolled and were randomly divided into two interventional groups. Fourteen patients were lost to follow-up. Group I (control) which had 66 patients received conservative management of CKD consisting of alpha-keto analogue (600 mg tablet three times a day), whereas Group II (test) which had 70 patients received conservative management along with alpha-keto analogue and N. sativa oil (2.5 mL, per orally, once daily) for 12 weeks. Hemogram, renal function, and serum electrolyte tests were done, and adverse events were recorded at baseline and at4, 8, and 12 weeks of treatment. After 12 weeks of treatment, there was a marked improvement in clinical features and biochemical parameters in both the control and test groups. There were a significant reduction in blood urea, serum creatinine, and 24-h total urine protein and a significant improvement in 24-h total urine volume and glomerular filtration rate. N. sativa oil supplementation along with alpha-keto analogue is more more efficacious and safe in delaying the progression of disease patients with CKD Stages 3 and 4.


Strap: a versatile transcription co-factor.
The Stress-responsive activator of p300 (Strap) is a transcription co-factor that has an important role in the control of DNA damage response through its ability to regulate p53 activity. Recent studies have however suggested that Strap takes on a wider role in regulating the cellular response to stress. Thus, Strap is now known to be inducible by heat shock and stimulate the transcription of heat-shock genes. A chromatin-associated complex involving heat-shock factor 1 (HSF1), Strap and the p300 co-activator assembles on the HSP70 gene promoter, and Strap augments HSF1 binding and chromatin acetylation in HSP genes, most probably through recruiting p300 acetyltransferase. Cells depleted of Strap do not survive under heat-shock conditions. It appears therefore that Strap is an essential co-factor that acts at the level of chromatin control to regulate heat-shock-responsive transcription. These recent studies underscore the central role taken on by transcription co-factors in integrating and co-ordinating different cellular stress response pathways.


Strategies for Partitioning Clock Models in Phylogenomic Dating: Application to the Angiosperm Evolutionary Timescale.
Evolutionary timescales can be inferred from molecular sequence data using a Bayesian phylogenetic approach. In these methods, the molecular clock is often calibrated using fossil data. The uncertainty in these fossil calibrations is important because it determines the limiting posterior distribution for divergence-time estimates as the sequence length tends to infinity. Here, we investigate how the accuracy and precision of Bayesian divergence-time estimates improve with the increased clock-partitioning of genome-scale data into clock-subsets. We focus on a data set comprising plastome-scale sequences of 52 angiosperm taxa. There was little difference among the Bayesian date estimates whether we chose clock-subsets based on patterns of among-lineage rate heterogeneity or relative rates across genes, or by random assignment. Increasing the degree of clock-partitioning usually led to an improvement in the precision of divergence-time estimates, but this increase was asymptotic to a limit presumably imposed by fossil calibrations. Our clock-partitioning approaches yielded highly precise age estimates for several key nodes in the angiosperm phylogeny. For example, when partitioning the data into 20 clock-subsets based on patterns of among-lineage rate heterogeneity, we inferred crown angiosperms to have arisen 198-178 Ma. This demonstrates that judicious clock-partitioning can improve the precision of molecular dating based on phylogenomic data, but the meaning of this increased precision should be considered critically.


Multiplexed surrogate analysis of glycotransferase activity in whole biospecimens.
Dysregulated glycotransferase enzymes in cancer cells produce aberrant glycans--some of which can help facilitate metastases. Within a cell, individual glycotransferases promiscuously help to construct dozens of unique glycan structures, making it difficult to comprehensively track their activity in biospecimens--especially where they are absent or inactive. Here, we describe an approach to deconstruct glycans in whole biospecimens then analytically pool together resulting monosaccharide-and-linkage-specific degradation products ("glycan nodes") that directly represent the activities of specific glycotransferases. To implement this concept, a reproducible, relative quantitation-based glycan methylation analysis methodology was developed that simultaneously captures information from N-, O-, and lipid linked glycans and is compatible with whole biofluids and homogenized tissues; in total, over 30 different glycan nodes are detectable per gas chromatography-mass spectrometry (GC-MS) run. Numerous nonliver organ cancers are known to induce the production of abnormally glycosylated serum proteins. Thus, following analytical validation, in blood plasma, the technique was applied to a group of 59 lung cancer patient plasma samples and age/gender/smoking-status-matched non-neoplastic controls from the Lung Cancer in Central and Eastern Europe (CEE) study to gauge the clinical utility of the approach toward the detection of lung cancer. Ten smoking-independent glycan node ratios were found that detect lung cancer with individual receiver operating characteristic (ROC) c-statistics ranging from 0.76 to 0.88. Two glycan nodes provided novel evidence for altered ST6Gal-I and GnT-IV glycotransferase activities in lung cancer patients. In summary, a conceptually novel approach to the analysis of glycans in unfractionated human biospecimens has been developed that, upon clinical validation for specific applications, may provide diagnostic and/or predictive information in glycan-altering diseases.